Cholecystokinin (CCK) and related molecules constitute a family of polypeptide hormones that are widely distributed in various parts of the body including the gastrointestinal tract and endocrine glands as well as peripheral and central nervous systems. A 33-amino acid fragment of CCK (CCK-33) was first isolated from hog intestines (Mutt and Jorpes, Biochem. J., 1971, 125: 628) and has subsequently been identified as a neurotransmitter (Rehfeld, J. Neurochem., 1985, 448: 1-8). CCK-33 and two smaller fragments, CCK-8 and CCK-4, also have been identified in the brain (Dockray, Nature, 1979, 264: 402), with CCK-8 being the predominant form there.
In the periphery, CCK plays a variety of regulatory roles, including stimulation of gallbladder contraction, pancreatic enzyme secretion and insulin secretion, and inhibition of gastric emptying. In addition, the high concentrations of CCK and CCK receptors found in the brain support the idea that a major brain function exists for this peptide. CCK has been suggested to have central actions in appetite control, schizophrenia, memory and cognition. Also, modulators of CCK actions may have potential as therapeutic agents for drug abuse.
Two sub-types of CCK receptors have been identified. Type-A receptors are found predominantly in the periphery and have high affinity for CCK-8 and low affinity for desulfated CCK-8 and CCK-4. Type-B receptors are found predominantly in the brain and have high affinity for CCK-8, desulfated CCK-8 and CCK-4. CCK-8 and desulfated CCK-8 were shown to be equipotent in enhancing learning and memory in mice and monkeys (Pietrusiak et al., Soc. Neurosci. Abstr., 1988, 13: 1030), which suggests that these actions are mediated by Type-B CCK receptors. Moreover, Hughes et al. (Proc. Natl. Acad. Sci., U.S.A., 1990, 87: 6728-6732) reported the potent and selective activity of two non-peptide CCK-B antagonists, PD134308 and PD135158, as anxiolytic agents. This finding suggests that the CCK-B receptor plays an important role in anxiety states.
Tetragastrin, the C-terminal tetrapeptide of the hormone gastrin, is fully active in stimulation of gastric acid release when compared to the native hormone and is identical to CCK-4, the C-terminal tetrapeptide of cholecystokinin. In addition, gastrin receptors and CCK-type-B receptors share many similarities with respect to ligand binding profiles. They have not yet been clearly demonstrated to be distinct, although their environments are distinctly different, i.e., gastric mucosa vs. brain cortex.
Considerable literature exists on structure-activity relationships of tetragastrin and related analogs with respect to gastric acid release. Morley et al. have synthesized a large number of tetragastrin analogs that explore C-terminal, N-terminal, and single amino acid modifications (Nature, 1965, 207: 1356; Proc Roy. Soc B. 1968, 170:97-111; Fed Proc. 1968, 27:1314; J. Chem. Soc. C. 1969, 5:809-13; U.S. Pat. No. 3,896,103 (1975)).
Cipens et al. (Khim Prir. Soedin. 6:117-119 (1970)) report Trp replacements in tetragastrin comprising 1-naphthylpropionic acid, 2-naphthylpropionic acid, naphthylacrylic acid and N.sup.in -Me-Trp, and Japanese Patent 71009454 (1971) reports Ala-Gly-Asp-Phe-NH.sub.2 and amino-protected derivatives of tetragastrin that inhibit gastric acid secretion. Japanese Patent 71016743 (1971) reports tetragastrin analogs, in which Gly is substituted for Asp, that inhibit gastric acid secretion and possess antitumor activity, and Japanese Patent 71017234 (1971) reports tetragastrin analogs in which beta-methylAsp is substituted for Asp, which stimulate gastric acid secretion.
Japanese Patent Application JA7138992 (1971) discloses the preparation of protected forms of Trp-Met-Asp-Phe-NH.sub.2, and German Patent Application DE2245459 (1973), discloses the preparation of N-protected forms of that peptide. Higaki et al. (Pharmacometrics 1974, 8:147-155) reported on structure-activity relationships of various N-acylated and amino acid-substituted analogs of tetragastrin with respect to gastric acid secretion in the rat, with tri-, tetra- and pentapeptides being tested, of which only peptides with Leu and Val substituted for Met and those with hydrazide substituted for C-terminal amide had significant activity.
Kisfaludy et al. (U.S. Pat. No. 4,183,909 (1980)) report tetragastrin analogs wherein Phe is replaced by phenylglycine and Met is replaced by Leu, Ile, Nva or 2-aminodecanoic acid, and Zarandi et al. (Peptides 1982, Walter de Gruyter & Co., Berlin & N.Y., 1983, pp 577-581) report biological activity in tetragastrin analogs wherein Trp is substituted by FMOC (9-fluorenylmethyloxycarbonyl).
Romanovski et al. (Russian patent SU624911 (1978)) report N-acylated pentapeptide analogs with succinyl-sarcosine in the N-terminal position that stimulate gastric acid secretion., and U.S. Pat. No. 4,172,130 (1979) reports analogs with novel N-protecting groups in which Met is substituted by Leu, Ile, Nle, Nva or 2-aminodecanoyl, which also have gastric acid stimulating activity. Charon et al. (U.S. Pat. No. 4,530,837 (1975)) report new pentapeptide analogs with Asp substituted by other dicarboxylic acids or substituted with various amides at the omega carboxyl group for use as gastric secretion inhibitors.
European Patent Application EP0239716, to Bertolini et al. (1987), discloses fragments of gastrin containing the peptide Trp-Met-Asp-Phe-NH.sub.2 for the therapy of shock and of respiratory and cardiocirculatory insufficiencies. The interaction of several CCK-4-related peptides with CCK-B receptors was reported by Horwell (J. Med. Chem., 1987, 30: 729), and a pentapeptide analog of CCK-5 with an N-methylnorleucine residue in place of Met was recently reported to have high affinity and selectivity for CCK-B receptors (Hruby et al., Intl. J. Peptide Protein Res., 1990, 35:566-573).
Larger peptides related to CCK are known to interact non-selectively with CCK-A and CCK-B receptors. U.S. Pat. No. 4,490,364 (Rivier et al., 1984), discloses heptapeptide, octapeptide and nonapeptide analogs of CCK-8 as agents for stimulating gallbladder contractions, arresting the secretion of gastric acid and treating convulsions. Recently, larger peptides selective for the CCK-B receptor have been reported (Charpentier et al., Peptides 1988 (1989) 9:835; Charpentier et al., Proc. Natl. Acad. Sci. USA, 1988, 85:1968; Rodriguez et al., Int. J. Peptide Protein Res. 1990, 35:566; Hruby et al., Int. J. Peptide Protein Res. 1990, 35:441).
A review that discusses CCK agonists and antagonists has recently appeared (Nadzan and Kerwin, Annual Reports in Medicinal Chemistry 1991, 26:191-200, Academic Press, N.Y.).